Clinical Development of Gene Therapies

Clinical Development of Gene Therapies

Alexander: [00:00:00] Welcome to another episode of the Effective Statistician. Today I’m super excited to have Oscar with me here and we will talk about clinical development plans for gene and cell therapy and how these then help to move into the post commercialization phase.

But before we dive a little bit further into that topic maybe you can introduce yourself shortly.

Oscar: Sure. First of all, Alexander, thank you so much for this opportunity to speak with you and your audience. I’m an MD, PhD. I work in academia for about 10 years, and I was able to get a PhD. Tenure professorship of immunology and at that time I started to think, okay, I already did this.

What do I do next? And in the next almost over 30 years now, I’ve been working in the biopharma industry. I’ve working also in med tech, [00:01:00] medical devices, and lately in biotechs and working with biotechs. That’s where I had the opportunity to focus on gene and cell therapies. What we’re going to be discussing today and the majority of my work first, when I work with what I would say my call to fame was with AbbVie, Abbott Laboratories or with the Humira team.

It was a biologic anti TNF, very well known, probably until recently with the new obesity drugs. best selling drug in history. And then I started working after my clinical development work also medical affairs with this company and with this asset. I moved into biotechs and my, my jobs at biotechs were always overseeing the entire clinical development effort.

And what that means is the majority of my roles were either supporting or being the chief medical officer. I recently [00:02:00] resigned from my last job. I there were a number of changes in my life and I decided to move back into consulting and that’s what we’re, what I’m doing right now. I run a, an organization called Medic Affairs Consulting LLC and I provide support for clinical development, for medical affairs across different therapeutics area, areas and I cover across different types of needs for my clients.

Alexander: Today, we want to talk a little bit specifically, not about this big blockbuster drugs like Humira. And yeah, I’ve worked on competitions of Humira quite a lot. But about exactly the opposite. Yeah. Gene and cell therapy. If you think about your kind of. History working on Jumeirah and on indications probably like psoriasis, rheumatoid arthritis and all these other diseases in this area where there’s, lots of patients.

And now you jump [00:03:00] into gene and cell therapy from a clinical development point of view. That must be a huge difference, isn’t it?

Oscar: Yeah, it’s very different. But look, when you’re an immunologist by background the first thing that you do is to understand the science

and what that means is that you’re a molecular biologist, you’re a protein biologist and a cell biologist.

So that’s why when I had the opportunity to rethink my career, and it was about 10 years ago, and I started going into this chief medical officer and this opportunity in gene and cell therapies, I realized, okay, I’m ready. I think especially gene therapy is going to be very easy to do. And that’s absolutely right.

And I was right, because you understand the biology of the target, which is a gene that either is not functioning or missing, and you just want to replace it. So from a drug development perspective, you know what you’re doing. And the possibility of failure [00:04:00] is very low. And I can jump into my last

Alexander: You just made a statement that I want to dig a little bit deeper into.

Why is the possibility of failure so low? Is it, don’t you? You still need to do phase one studies and so on, isn’t it?

Oscar: Yeah, you do. But again, you know exactly what’s the problem. And you have the solution. Nowadays, gene therapies has been, have been going on for over 20 years in humans, obviously much earlier than that in preclinical work.

And during all these two decades, we know exactly how to synthesize a gene In the lab, and to put together all the elements that you need to trigger the activity of this gene. We also know how to incorporate this gene into an individual. In my case, [00:05:00] where I was focusing in one of my roles, supporting a chief medical officer, was into the motor neurons working with a vexus.

which was acquired by Novartis for over seven billion dollars, and I worked with that team, and they, they were able to incorporate a gene into these motor neurons of little babies that would die within months.

Okay. And many of them have been already alive for over 10 years. So the f my focus was on, on incorporating or inserting these genes into the liver, which is even more, more, let’s say possible with different therapeutic areas.

And the way I do that was focusing on hemophilia A. . There is also hemophilia B. In both cases, you have a non functional or missing gene for factor VIII. Factor VIII is part of the cascade of the coagulation so that you are able, your blood is able to [00:06:00] clot. We know for many years, for decades even, that even in hemophilia A, that if you replace those, the missing gene for factor VIII, this patient is going to be able to sustain.

This activity factor it for life and that’s where I can go into more details and that’s what I was doing for the past four and a half years.

Alexander: So the method of action is absolutely clear. Yeah very

Oscar: well defined has been developed. There are many companies working on these. ISC therapeutics is a small biotech in the Bay Area, but you have Pfizer collaborating with Sangamo.

They just announced that they have also a factor eight gene available. You have Roche. They acquired Spark Therapeutics, and they also have developed another gene therapy for hemophilia A, and there is also BioMarine. And [00:07:00] this is the only approved factor eight for for I can go into the details why we were doing that when our competition was so big and strong.

Alexander: If you know the method of action, yeah, and I know I’ve worked in psychiatry and these kind of areas, and there’s everything, but the method of action is very clear because in, the brain is so complex that you think you understand a couple of things, but there’s so many different factors involved, yeah.

And then. You, but you still need to do your phase one studies to assure that your drug is safe and you have the right dose. If, and then I think with gene therapy, you only have more or less one goal per patient, isn’t it? So you say you can’t have a dose escalation or anything like that, isn’t it?

Oscar: That’s correct. So you the reason for that is that we use [00:08:00] AAV, an adeno associated virus, and we give to the patient this virus containing the synthesized gene.

Plus all the elements that are necessary to ensure that the genes function once you insert that into the liver cell, the hepatocyte. And because you use such an incredible amount of viruses, in the trillions of viruses, this patient develops an immune response and becomes totally immune. Unable to receive another time, another goal with any other AAV.

So any patient receiving a gene therapy. Cannot receive any other gene therapy using this methodology, which is, which we call AAV gene therapies. So you’re right. So you get so you do all your pre analytical work on animal models, on, on monkeys. And once you have it identified, [00:09:00] you have usually two or three doses that you want to test in patients.

And then you have a dose escalation. Phase one to eight, we call because we don’t have a phase two, so we move from the Only pre pivotal trial study to the pivotal trial. And in that study, we define the actual dose that you need to the patient, but we can use that one dose per patient. We see how it works.

Then we go to the next patient. So we treat in general three to four patients with one dose. We move to the next cohort and to the next cohort, and we decide which one is working.

And I can tell you with ASC Therapeutics, we were able to treat the first cohort, it worked very nicely, and we were able to start preparing for the second cohort.

I found it, to tell you the truth, a little bit boring because it takes forever to do these clinical trials. We had already a number of competitors doing very well, but we had a specific and a different type of gene therapy that [00:10:00] brought another different shape to the patient. differentiating factor that we think we thought, I thought when I was with the company would be very helpful.

So indeed you still need a phase one clinical trial. And this is just between eight to 12 patients. It’s not much, not more than one.

Alexander: So I have another question. So if we basically just replace the gene. How do we then have different drugs? Aren’t then all the drugs more or less exactly the same?

Isn’t that all basically copies of the original drug? Because that, that, that’s just my naive question. Yeah. So if you have, if you think about, for example, Humira, yeah. Says, lots of different NTTLFs, and they are all different biological entities, yeah?

They all have a little bit of a different method of action, and so on, different binding affinity, and all these kind of different things. [00:11:00] And my assumption my very naïve assumption, being just a statistician if you will, replacing a gene is basically always exactly the same. What’s the difference between the different drugs then?

Oscar: This is an ex excellent question, and that’s also what I would wonder, and you would say, why did I do that? Having three top competitors, one of them already an f, d, a, approved, why would I do this? And going into this space. First of all, because it’s hemophilia A. So this is, although this is a rare disease, it’s very common, relatively common as a rare disease, and there is a huge market.

So when the entire process of developing of these drugs started about, I would say, about 10 years ago now, believe it or not, the actual effort by Pfizer, Roche, and Biomarin, we hadn’t started yet, Everyone thought, okay, my God, this is a [00:12:00] huge market, relatively. Everyone started to think a lot in gene therapies or diseases.

But you are absolutely right. All the gene therapies, all these three companies working on gene therapies, would do basically the same thing. There is no patent protection or something like that. Genes cannot be patented. It’s all about methodology. It’s about little details about how do you produce your gene therapy?

How do you deliver it?

Alexander: Yeah.

Oscar: What the dose and what are your costs? At the end of the day, you afford that. Everyone afford that, that these therapies are externally costly are between I would say one and three million dollars per patient per dose to treat the patient only once and in some cases like recently in the UK, NICE, which is the reimbursement agency in the UK just approved one of these drugs for this.

Alexander: So really [00:13:00] the differences are in The delivery. So the you talked about the, it’s basically sent through a virus into the and I think this kind of virus capture capsule, so to say, that can be different, isn’t it? So that is more the methodology around it. Is that correct?

Oscar: Yeah. For instance, we use different types of AAV. They are numbered from one to 10. And some people use AB5, others AB8, others AB9, and so on. And that could be one difference. But at the end of the day, believe it or not, it doesn’t matter. The moment that you get one of these AAVs, it doesn’t matter which one.

You are going to be immunized for all other AAVs. As I said at the beginning. So that’s the first thing to take into account. Now. What that does one difference, but another difference is be able to have a very low dose.

If you [00:14:00] have a low dose because of the high cost of manufacturing, you’re going to be able to reduce the cost of your therapy.

That’s something that is important and everyone is trying to do that. Now, What happened in AAV and why I got out of that I mean with Hemophilia A and why I decided to get out of that space is because Roche came up with a Phenomenal way to treat patients with hemophilia A so that they would not need to to go as what happens with these patients practically they need to go into, in, in their hospitals in a regular base basis, even twice a week.

So when this new drug came to the market, everyone started realizing, okay, we are. We gene therapy is losing totally the value for these patients. And this is what has happened. Biomarine launched the drug over one and a half years ago. And they want to divest that [00:15:00] asset.

It has a complete disaster. Economically for the company, they replaced the CEO. And I think they sold in two years or in one half year, maybe they were able to treat five to 10 patients or something like that, absolutely catastrophic. We were bringing